Combination product for controlling parasites on animals

ABSTRACT

The invention relates to novel compositions for controlling parasites on animals, comprising an N-arylpyrazole and also a pyrethroid in a formulation comprising aliphatic cyclic carbonates and aliphatic cyclic or acyclic polyethers.

The invention relates to novel compositions for controlling parasites onanimals, comprising an N-arylpyrazole and also a pyrethroid in aformulation comprising aliphatic cyclic carbonates and aliphatic cyclicor acyclic polyethers.

N-Arylpyrazoles and their good insecticidal and acaricidal activity areknown from US 2006014802 A1, WO2005090313 A1, FR2834288 A1, WO09828277,U.S. Pat. No. 06,069,157, WO200031043, DE19824487, WO09804530,WO09962903, EP00933363, EP00911329, WO09856767, U.S. Pat. No.05,814,652, WO09845274, WO9840359, WO09828279, WO09828278, DE19650197,WO09824767, EP00846686, EP00839809, WO09728126, EP00780378, GB02308365,U.S. Pat. No. 05,629,335, WO09639389, U.S. Pat. No. 05,556,873,EP00659745, U.S. Pat. No. 05,321,040, EP00511845, EP-A-234119,EP-A-295117 and WO 98/24769. In spite of this abundance of applicationswith numerous N-arylpyrazole structures, there is a superior structuretype which, for most indications, shows, by comparison, the bestactivity.1-[2,6-Dichloro-4-(trifluoromethyl)phenyl]-3-cyano-4-[(trifluoromethyl)-sulphinyl]-5-aminopyrazole(INN: fipronil) is generally acknowledged to be the most effectivecompound of this class for controlling most parasites.

N-Arylpyrazoles have been marketed as ectoparasiticides for more than 10years (Hunter, J. S., III, D. M. Keister and P. Jeannin. 1994. Fipronil:A new compound for animal health. Proc. Amer. Assoc. Vet. Parasitol.39th Ann. Mtg. San Francisco, Calif. Pg. 48.). They are distinguished bygood and broad activity and acceptable compatibility. It is known thatthe existing formulations having a high content of DEE (Transcutol)contain a strong transdermal (FR 1996-11446 A; Sicherheitsdatenblatt[Safety data sheet]: ISO/DIS 11014/29 CFR 1910.1200/ANSI Z400.1 Printingdate Oct. 23, 2001: FRONTLINE® TOP SPOT™: fipronil 9.7% w/w) component.This facilitates, via the formulation, penetration into the sebaceousglands and the epithelium (Skin distribution of fipronil bymicroautoradiography following topical administration to the beagle dog.Cochet, Pascal; Birckel, P.; Bromet-Petit, M.: Bromet, N.: Weil, A.;European Journal of Drug Metabolism and Pharmacokinetics (1997), 22(3),211-216.). Via sebum excretion from the sebaceous glands, a highconcentration in the sebaceous glands may contribute to a long-lastingavailability of the active compound if the active compound is carriedalong. However, in the case of the customary formulations, penetrationof N-arylpyrazoles into the circulation is also likely, since each hairfollicle is supplied by a blood vessel and the follicles are thusseparated from the circulation only by a very thin barrier(Transfollicular drug delivery—Is it a reality? Meidan, Victor M.;Bonner, Michael C.; Michniak, Bozena B.; International Journal ofPharmaceutics (2005), 306(1-2), 1-14). Thus, the availability of theactive compound on the animal is limited, too, both with respect toduration and concentration, since the active compound passes into thecirculation and its available concentration in the sebum is loweredaccordingly.

It is further known that the efficacy of the N-arylpyrazoles againstrepresentatives of the genus Ixodes is less than that against othergenera of ticks (Endris R G, Matthewson, Cooke D & Amodie D (2000).Rellency and efficacy of 65% permethrin and 9.7% fipronil against Ixodesricinus. Vet. Therapeutics, Vol. 1 (No, 3): 159-168); Endris R G, CookeD, Amodie D, Sweenwy D L & Katz T L (2002). Repellency and efficacy of65% permethrin and selamectin spot-on formulations against Ixodesricinus on dogs. Vet. Therapeutics. Vol. 3 (No. 1): 64-71).

Pyrethroids do likewise have a relatively broad insecticidal action, andsome representatives also show good acaricidal effects; however, withthese compounds there are frequently incompatibilities, and onlyparticularly non-toxic representatives with limited efficacy can be usedfor cats. Recently, WO 04/098290 described a solution of this problemwhere a dosage tolerated by cats could be achieved with the aid of asynergist, an acaricidal pyrethroid and a neonicotinoid. The differentphysicochemical properties of the materials used require specialformulations.

Furthermore, it is generally known that, compared to N-arylpyrazoles,pyrethroids are less active against ticks of the genus Dermacentor.Recently, it has furthermore been found that there is nocross-resistance between pyrethroids and N-arylpyrazoles inpyrethroid-resistant insects. On the other hand, selection of suchmosquito strains with N-arylpyrazoles even leads to partial reversion ofthe pyrethroid resistance.

[Laboratory evaluation of fipronil, a phenylpyrazole insecticide,against adult Anopheles (Diptera: Culicidae) and investigation of itspossible cross-resistance with dieldrin in Anopheles stephensi.Kolaczinski, Jan; Curtis, Chris. London School of Hygiene and TropicalMedicine, London, UK. Pest Management Science (2001), 57(1), 41-45].

WO 2001/065941 A1 and EP 1013170 A1 propose the combination of anN-arylpyrazole and a pyrethroid in applications against plant pests. JP11049618 A2 uses similar mixtures to prevent feeding damage on timberconstructions. WO 95/22902 A1 uses such mixtures for the direct controlof termites. FR 2713891 A1 and WO 95/22902 A1 even claim a synergisticeffect of such mixtures, but without demonstrating it clearly.

However, [Antagonism of fipronil toxicity by piperonyl butoxide andS,S,S-tributyl phosphorotrithioate in the German cockroach (Dictyoptera:Blattellidae). Valles, Steven M.; Koehler, Philip G.; Brenner, RichardJ. Center for Medical, Agricultural and Veterinary Entomology, USDA-ARS,Gainesville, Fla., USA. Journal of Economic Entomology (1997), 90(5),1254-1258] indicates that inhibitors of the oxidative metabolism (P450oxidase inhibitors) have an antagonistic effect in cockroaches on theaction of N-arylpyrazoles. Since most pyrethroids are detoxified via thep450 oxidase path, they, like MGK264 or piperonyl butoxide, have to beconsidered to be antagonists rather than synergists of theN-arylpyrazoles.

GB2396557 A1 teaches that the treatment of ectoparasites with mixturesof N-arylpyrazoles and pyrethroids (if appropriate also with addition ofsynergists, such as MGK264 or piperonyl butoxide) is possible whenconcentrated powder formulations are used. WO 95/22902 A1 describes asoil treatment with improved activity by combined application ofphenylpyrazoles and pyrethroids for control of termites. Here, too, themixture used is unsuitable for application on homeotherms.

Since such formulations are difficult to apply in practice and, owing tothe particles (GB 2396557), involve additional toxicological risks, ithas to be the object to prepare a self-spreading liquid formulationhaving a good user safety profile which combines the positive activityproperties of the pyrethroids with those of the N-arylpyrazoles and doesnot result in a reduction of the efficacy of the N-arylpyrazoles even inthe presence of further synergists from the class of the p450 oxidaseinhibitors.

To this end, by intensive analyses and test series, we have nowidentified, from a large number of additives, solvents and spreadingagents, formulations which, in general, can improve the goodarthropodicidal efficacy properties of the N-arylpyrazoles incombination with pyrethroids. Surprisingly, the expected antagonisticeffects were not observed here.

The invention relates to novel compositions for controlling parasites onanimals, comprising an N-arylpyrazole and a pyrethroid in a formulationcomprising:

-   -   an aliphatic cyclic carbonate    -   an aliphatic cyclic or acyclic polyether.

The arthropodicidal compositions according to the invention are noveland, compared to the formulations hitherto described, have considerablybetter and longer-lasting efficacy, with simultaneously improved userand target animal safety profile.

For the compositions, the combination partners of the N-arylpyrazolesare preferably arthropodicidal pyrethroids, in particular of thecyanopyrethroid (for example flumethrin), type-1 pyrethroid (for examplepermethrin) or non-ester pyrethroid (etofenprox) type.

Here, α-cyanopyrethroids (for example alpha-cypermethrin, cyfluthrin,beta-cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate,flucythrinate, flumethrin, tau-fluvalinate) are preferably employed in aconcentration range of from 0.01 to 5% by weight, and a synergist isadded, if appropriate (as described, for example, in WO 04/098290).Particular preference is given to using cypermethrin, cyfluthrin,deltamethrin and flumethrin in a concentration range of from 0.025 to0.25% by weight. Very particular preference is given to using flumethrinin a concentration range of from 0.05 to 1.25% by weight.

Type-1 pyrethroids (for example allethrin, bioallethrin, permethrin,phenothrin, resmethrin, tetramethrin, transfluthrin) are preferablyemployed in a concentration range of from 20 to 70% by weight.Particular preference is given here to permethrin, cyphenothrin in aconcentration range of from 30 to 60% by weight. Very particularpreference is given to using permethrin in concentrations of from 40 to50% by weight.

Non-ester pyrethroids (for example etofenprox, halfenprox, silafluofen)are usually employed in a concentration range of from 10 to 60% byweight. Preference is given to etofenprox or halfenprox; particularpreference is given to etofenprox in a concentration range of 25-55%.

To the person skilled in the art, N-arylpyrazoles are known per se asarthropodicidally active compounds, for example from the documentsmentioned above, which are incorporated herein by way of reference.

Preferred phenylpyrazoles are those of the formula (1):

in which

-   -   X represents ═N— or C—R¹,    -   R¹ and R³ independently of one another represent halogen,    -   R² represents halogen, C₁₋₃-haloalkyl, S(O)_(n)CF₃ or SF₅,    -   n represents 0, 1 or 2,    -   R⁴ represents hydrogen, cyano or a radical of the formula

-   -   -   or one of the cyclic substituents below:

-   -   R⁵ represents hydrogen, C₂₋₄-alkynyl, C₂₋₄-alkenyl which may        optionally be mono- or polysubstituted by halogen or C₁₋₃-alkyl,        or R⁵ represents C₁₋₄-alkyl-(C═O)—, C₁₋₄-alkyl-S—,        C₁₋₄-haloalkyl-S—, —S(═O)—C₁₋₄-alkyl or —S(═NH)—C₁₋₄-alkyl,        optionally halogen-substituted phenyl, optionally        halogen-substituted furyl, the radical —NR¹⁴R¹⁵, an oxiranyl        radical which is optionally mono- or polysubstituted by        C₁₋₄-alkyl or C₁₋₄-haloalkyl, or a cyclopropyl radical which is        optionally mono- or polysubstituted by halogen, C₁₋₄-alkyl or        C₁₋₄-haloalkyl,    -   R⁶ represents hydrogen, C₁₋₄-alkylcarbonyl or a radical        —NR¹⁶R¹⁷,    -   R⁷ represents hydrogen, C₁₋₄-alkyl, C₁₋₄-alkyl-S— or —NR⁹R¹⁰,    -   Y represents ═S, ═O, ═NH, ═N—C₁₋₄-alkyl, ═N—OH or

-   -   R⁸ represents C₁₋₄-alkyl,    -   R⁹ and R¹⁰ independently of one another represent hydrogen,        hydroxyl or C₁₋₄-alkyl,    -   R¹¹ represents hydrogen, C₁₋₄-alkyl, —COO—C₁₋₄-alkyl or        —CONR¹²R¹³,    -   R¹² and R¹³ independently of one another represent hydrogen or        C₁₋₄-alkyl,    -   R¹⁴ and R¹⁵ independently of one another represent hydrogen,        C₁₋₄-alkyl, C₁₋₄-haloalkyl or C₁₋₄-alkyl-SO₂—,    -   R¹⁶ and R¹⁷ independently of one another represent hydrogen,        C₁₋₄-alkoxy or C₁₋₄-alkyl, where the C₁₋₄-alkyl may optionally        be substituted by phenyl, pyranzinyl or pyridyl, where phenyl,        pyranzinyl or pyridyl may be mono- or polysubstituted by        hydroxyl, C₁₋₄-alkyl, C₁₋₄-haloalkyl and/or C₁₋₄-alkoxy, or    -   R¹⁶ and R¹⁷ represent C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl,        C₁₋₄-alkoxy-C₁₋₄-alkylcarbonyl or the radical —(C═O)NR²⁰R²¹ or    -   R¹⁶ and R¹⁷ together represent the group ═CR¹⁸R¹⁹ which is        attached by a double bond to the nitrogen,    -   R¹⁸ and R¹⁹ independently of one another represent phenyl which        is optionally mono- or polysubstituted by hydroxyl, C₁₋₄-alkyl,        C₁₋₄-haloalkyl and/or C₁₋₄-alkoxy, and/or R¹⁸ and R¹⁹ represent        hydrogen, C₁₋₄-alkyl, C₁₋₄-alkenyl or C₁₋₄-alkoxy, where        C₁₋₄-alkyl, C₁₋₄-alkenyl or C₁₋₄-alkoxy may optionally be        substituted by phenyl which is optionally mono- or        polysubstituted by hydroxyl, C₁₋₄-alkyl, C₁₋₄-haloalkyl and/or        C₁₋₄-alkoxy,    -   R²⁰ and R²¹ independently of one another represent hydrogen,        C₁₋₄-alkyl or phenyl which is optionally mono- or        polysubstituted by hydroxyl, C₁₋₄-alkyl, C₁₋₄-haloalkyl and/or        C₁₋₄-alkoxy,    -   R²² represents C₁₋₄-alkyl.

Halogen preferably represents fluorine, chlorine, bromine or iodine, inparticular fluorine, chlorine or bromine.

C₁₋₄-Alkyl represents straight-chain or branched alkyl having 1 to 4carbon atoms, such as, for example, methyl, ethyl; n-propyl, isopropyl,n-butyl, sec-butyl, tert-butyl.

C₁₋₄-Haloalkyl represents straight-chain or branched alkyl having 1 to 4carbon atoms which is substituted by one or more identical or differenthalogen atoms; this also includes perhaloalkyl compounds. Preference isgiven to fluoroalkyls. Examples are —CF₂H, —CF₃, —CH₂CF₃, —CF₂CF₃.

Preferably, the substituents have the following meanings:

-   -   X preferably represents C—R¹.    -   R¹ and R³ independently of one another preferably represent        chlorine or bromine.    -   R² preferably represents C₁₋₃-haloalkyl or SF₅.    -   R⁴ preferably represents hydrogen, cyano or a radical of the        formula

-   -   -   or one of the cyclic substituents below:

-   -   R⁵ preferably represents hydrogen, C₂₋₃-alkynyl, C₂₋₃-alkenyl        which may optionally be monosubstituted by halogen or        C₁₋₃-alkyl, or R⁵ preferably represents C₁₋₃-alkyl-(C═O)—,        C₁₋₃-alkyl-S—, C₁₋₃-haloalkyl-S—, —S(═O)—C₁₋₃-alkyl or        —S(═NH)—C₁₋₃-alkyl, optionally halogen-substituted phenyl,        optionally halogen-substituted furyl, the radical —NR¹⁴R¹⁵, an        optionally C₁₋₃-haloalkyl-substituted oxiranyl radical or a        cyclopropyl radical which is optionally mono- or polysubstituted        by halogen, C₁₋₄-alkyl or C₁₋₄-haloalkyl.    -   R⁶ preferably represents hydrogen, C₁₋₃-alkylcarbonyl or a        radical —NR¹⁶R¹⁷.    -   R⁷ preferably represents hydrogen, C₁₋₄-alkyl, C₁₋₄-alkyl-S— or        —NR⁹R¹⁰.    -   Y preferably represents ═S, ═O, ═NH, ═N—OH or

-   -   R⁸ preferably represents C₁₋₃-alkyl.    -   R⁹ and R¹⁰ independently of one another preferably represent        hydrogen, hydroxyl or C₁₋₃-alkyl.    -   R¹¹ preferably represents hydrogen, C₁₋₄-alkyl or —CONR¹²R¹³.    -   R¹² and R¹³ independently of one another preferably represent        hydrogen or C₁₋₃-alkyl.    -   R¹⁴ and R¹⁵ independently of one another preferably represent        hydrogen, C₁₋₃-alkyl, C₁₋₃-haloalkyl or C₁₋₃-alkyl-SO₂—.    -   R¹⁶ and R¹⁷ independently of one another preferably represent        hydrogen, C₁₋₃-alkoxy or C₁₋₃-alkyl, where the C₁₋₃-alkyl may        optionally be substituted by phenyl, pyrazinyl or pyridyl, where        phenyl, pyrazinyl or pyridyl may be mono- or disubstituted by        hydroxyl, C₁₋₃-alkyl, C₁₋₃-haloalkyl and/or C₁₋₃-alkoxy, or    -   R¹⁶ and R¹⁷ represent C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl,        C₁₋₄-alkoxy-C₁₋₄-alkylcarbonyl or the radical —(C═O)NR²⁰R²¹ or    -   R¹⁶ and R¹⁷ together represent the group ═CR¹⁸R¹⁹ which is        attached by a double bond to the nitrogen.    -   R¹⁸ and R¹⁹ independently of one another preferably represent        phenyl which is optionally mono- or disubstituted by hydroxyl,        C₁₋₃-alkyl, C₁₋₃-haloalkyl and/or C₁₋₃-alkoxy, and/or R¹⁸ and        R¹⁹ represent hydrogen, C₁₋₃-alkyl, C₁₋₃-alkenyl or C₁₋₃-alkoxy,        where C₁₋₃-alkyl, C₁₋₃-alkenyl or C₁₋₃-alkoxy may optionally be        substituted by phenyl which is optionally mono- or disubstituted        by hydroxyl, C₁₋₄-alkyl, C₁₋₄-haloalkyl and/or C₁₋₄-alkoxy.    -   R²⁰ and R²¹ independently of one another preferably represent        C₁₋₃-alkyl or phenyl which is optionally mono- or disubstituted        by hydroxyl, C₁₋₃-alkyl, C₁₋₃-haloalkyl and/or C₁₋₃-alkoxy.    -   R²² preferably represents C₁₋₃-alkyl.

Particularly preferably, the substituents in formula (I) have themeaning below:

-   -   X represents C—R¹.    -   R¹ and R³ each represent Cl.    -   R² represents CF₃.    -   R⁴ represents CN, —C(═S)NH₂ or —C(═O)CH₃.    -   R⁵ represents —SCHF₂, —S(═O)CF₃, —S(═O)CH₃, —S(═O)CH₂CH₃ or        represents the 1-trifluoromethyloxiranyl radical.    -   R⁶ represents an amino group or one of the radicals below

Preferred examples of compounds which can be used according to theinvention are listed below:

Particularly preferred examples of compounds which can be used accordingto the invention are:

An example of a very particularly preferred N-arylpyrazole is fipronil.

A further example of a very particularly preferred N-arylpyrazole is5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-thio-carbamoylpyrazole.

Depending on the nature and arrangement of the substituents, the activecompounds may, if appropriate, be present in various stereoisomericforms, in particular as enantiomers and racemates. According to theinvention, it is possible to use both the pure stereoisomers andmixtures thereof.

If appropriate, the active compounds can also be employed in the form oftheir salts, pharmaceutically acceptable acid addition salts and basicsalts being suitable.

Suitable pharmaceutically acceptable salts are salts of mineral acids ororganic acids (for example carboxylic acids or sulphonic acids).Examples which may be mentioned are salts of hydrochloric acid,sulphuric acid, acetic acid, glycolic acid, lactic acid, succinic acid,citric acid, tartaric acid, methanesulphonic acid, 4-toluenesulphonicacid, galacturonic acid, gluconic acid, embonic acid, glutamic acid oraspartic acid. Suitable pharmaceutically acceptable basic salts are, forexample, the alkali metal salts, for example the sodium or potassiumsalts, and the alkaline earth metal salts, for example the magnesium orcalcium salts.

It is furthermore also possible to use the active compounds in the formof their solvates, in particular hydrates. Solvates are to be understoodas meaning both the solvates, in particular hydrates, of the activecompounds themselves and the solvates, in particular hydrates, of theirsalts.

As solids, the active compounds may, in certain cases, form variouscrystal modifications. Advantageous for the use in medicaments arestable modifications having suitable solubility properties.

Unless indicated otherwise, percentages are to be understood as per centby weight based on the weight of the finished preparation.

Usually, the compositions comprise the arylpyrazole in amounts of from 1to 27.5% by weight, preferably from 5 to 20% by weight, particularlypreferably from 7.5 to 15% by weight.

The aliphatic cyclic carbonate is preferably ethylene carbonate orpropylene carbonate, it also being possible to use mixtures.

The amount of aliphatic cyclic carbonate in the formulation can bevaried widely in the range of from 10% by weight to 70% by weight,preferably from 12.5 to 50% by weight, particularly preferably from 15to 40% by weight.

Aliphatic cyclic and/or acyclic ethers are compounds known per se.Preferably, they are ethers derived from diols having up to 8 carbonatoms, such as, for example, ethylene glycol, diethylene glycol,propylene glycol, dipropylene glycol. In the acyclic ethers, one or bothOH groups carry a C₁₋₄-alkyl group, preferably, only one OH group isetherified; particularly preferred examples are: diethylene glycolmonoethyl ether, diethylene glycol monopropyl ether, dipropylene glycolmonopropyl ether. Preferred 5- or 6-membered cyclic ethers have a ringoxygen and 4 or 5 ring carbon atoms and optionally carry a C₁₋₄-alkylsubstituent; preferably, they carry a free OH group either directly onthe ring or on the C₁₋₄-alkyl substituent. A particularly preferredexample is tetrahydrofurfuryl alcohol. The amount of aliphatic, cyclicand/or acyclic ether in the compositions according to the invention canbe varied within wide limits of from 20 to 77.5% by weight, with amountsin the range of from 25 to 65% by weight and amounts in the range offrom 25 to 50% by weight being particularly preferred and veryparticularly preferred, respectively.

According to a preferred embodiment, the compositions according to theinvention may additionally comprise one or more esters of a dihydric ortrihydric alcohol having up to three carbon atoms with organic fattyacids having 6 to 18 carbon atoms. As alcohol component, the esters usedaccording to the invention contain a di- or trihydric alcohol having upto three carbon atoms, such as, for example, ethylene glycol, propyleneglycol or glycerol. In general, at least two, preferably all, hydroxylgroups of the alcohol are esterified. The acid components of the estersare fatty acids having 6 to 18 carbon atoms, which may bestraight-chain, branched and also mono- or polyunsaturated. It ispossible to use mixed esters or else mixtures of various types ofesters. Preferred triglycerides are caprylic/capric acid triglyceridesand also caprylic/capric/linoleic acid triglycerides. Preference islikewise given to esters of propylene glycol with caprylic and/or capricacid (propylene glycol octanoate decanoate). Particularly preferably,these glycerol or propylene glycol esters of caprylic/capric acid have aviscosity range (20° C.) of 0.08-1.3 Pa·s, and preferably 0.08-0.40Pa·s. It is also possible to use their polyethylene oxide-,polypropylene oxide- and/or propylene carbonate-modified derivativeshaving the viscosity range mentioned. Examples which may be mentionedare propylene glycol dicaprylate, propylene glycol octanoate decanoatehaving a viscosity range of 0.09-0.12 Pa·s, caprylic/capric diglycerylsuccinate having a mean viscosity of 0.23 Pa·s, medium-chaincaprylic/capric triglycerides having a viscosity of 0.27-0.30 Pa·s.

The liquid formulations according to the invention may comprise one ormore of the esters mentioned above. Usually, the compositions accordingto the invention comprise the ester or the ester mixture in proportionsof from 0 to 40% by weight, preferably from 1 to 35% by weight,particularly preferably from 1 to 12.5% by weight and very particularlypreferably from 2.5 to 7.5% by weight.

If appropriate, customary organic or inorganic antioxidants may be usedfor stabilizing the formulations mentioned. Suitable inorganicantioxidants are, for example, the sulphites and bisulphites, inparticular sodium bisulphite. Preference is given to phenolicantioxidants, such as anisole, butylated hydroxytoluene andhydroxyanisole, and their mixtures with one another. Usually, from 0.01to 1% by weight, preferably from 0.05% to 0.5%, particularly preferablyfrom 0.075 to 0.2% by weight is used.

The formulation ingredients mentioned, in particular the organic esters,may be stabilized against possible hydrolytic degradation usingacidifying agents. Suitable acidifying agents are pharmaceuticallyacceptable acids, in particular carboxylic acids, such as, for example,succinic acid, tartaric acid, lactic acid or citric acid. Theirpreferred amount is in the range of from 0 to 0.5% by weight, butpreferably from 0 to 0.2% by weight.

Polymeric surfactants based on polymethoxysiloxanes having a low surfacetension of <30 mN/m, preferably <22 mN/m, can be used as furtherformulation auxiliaries for improving the spreadability. Suchsurfactants are known ethoxylated and/or propoxylated, preferablyneutral or particularly preferably cationic formulation auxiliaries. Anexample of a preferred polymeric auxiliary which may be mentioned is themethoxysilane/ethylene oxide copolymer Belisil Silvet L 77 from Bayer GESiliconics GmbH. The amount of these formulation auxiliaries may bevaried within wide limits in the range of from 0.01 to 1.0% by weight.The preferred range is from 0.2 to 0.4% by weight.

If appropriate, the formulations may comprise further pharmaceuticallyacceptable auxiliaries and additives.

In addition to the arylpyrazoles and pyrethroids, the compositionsaccording to the invention may also comprise one or more additionalactive compounds. Preferred examples of such active compounds forcombinations which may be mentioned are: growth inhibitors, such as, forexample, chitin biosynthesis inhibitors, such as, for example,benzoylphenylureas (for example triflumuron, lufenuron);phenyloxazolines (for example etoxazole); juvenile hormone analogues(for example methoprene, hydroprene, pyriproxifen) and also mixtures ofthese active compounds with one another. Their amount may be variedwithin wide limits in the range of from 0.1 to 7.5% by weight, butpreferably from 0.25 to 5.0% by weight, particularly preferably from0.25 to 2.5% by weight.

The formulations according to the invention may also comprisesynergists. Synergists in the sense of this application are to beunderstood as meaning compounds which for their part do not have thedesired activity, but which, as mixing partners, increase the activityof the active compounds. Piperonyl butoxide, MGK264, verbutin,S,S,S-tributyl phosphorotrithioate may be mentioned here in an exemplarymanner. In the formulations according to the invention, synergists arepreferably used for α-cyanopyrethroids, namely in a synergist:pyrethroidratio of 20-50:1 (see also WO 04/098290). The preferred synergist isMGK264.

The compositions according to the invention are environmentallycompatible and have a low toxicity which is reduced compared to that ofknown compositions. Accordingly, they are user-friendly and furthermoredistinguished by their easy handling. The compositions have a favourableflashpoint of >70° C. and can therefore be manufactured in simple plantswhich do not require additional measures to protect against explosions.

Having favourable homeotherm toxicity, the compositions of the inventionare suitable for controlling parasitic arthropods, in particular insectsand arachnids, very particularly fleas and ticks, encountered onanimals, in particular homeotherms, particularly preferably mammals.These animals may be domestic animals and useful animals and also zooanimals, laboratory animals, test animals and pets.

The compositions described herein are used in particular againstectoparasites on pets, in particular dogs and cats, and useful animals.

The compositions of the invention are active against all or individualstages of development of the pests and against resistant and normallysensitive pest species.

The pests include:

from the order of the Anoplura, for example, Haematopinus spp.,Linognathus spp., Solenopotes spp., Pediculus spp., Pthirus spp.;

from the order of the Mallophaga, for example, Trimenopon spp., Menoponspp., Eomenacanthus spp., Menacanthus spp., Trichodectes spp., Felicolaspp., Damalinea spp., Bovicola spp;

from the order of the Diptera, suborder Brachycera, for example,Chrysops spp., Tabanus spp., Musca spp., Hydrotaea spp., Muscina spp.,Haematobosca spp., Haematobia spp., Stomoxys spp., Fannia spp., Glossinaspp., Lucilia spp., Calliphora spp., Auchmeromyia spp., Cordylobia spp.,Cochliomyia spp., Chrysomyia spp., Sarcophaga spp., Wohlfartia spp.,Gasterophilus spp., Oesteromyia spp., Oedemagena spp., Hypoderma spp.,Oestrus spp., Rhinoestrus spp., Melophagus spp., Hippobosca spp.

from the order of the Diptera, suborder Nematocera, for example, Culexspp., Aedes spp., Anopheles spp., Culicoides spp., Phlebotomus spp.,Simulium spp.

from the order of the Siphonaptera, for example, Ctenocephalides spp.,Echidnophaga spp., Ceratophyllus spp., Pulex spp.

from the order of the Metastigmata, for example, Hyalomma spp.,Rhipicephalus spp., Boophilus spp., Amblyomma spp., Haemaphysalis spp.,Dermacentor spp., Ixodes spp., Argas spp., Ornithodorus spp., Otobiusspp.;

from the order of the Mesostigmata, for example, Dermanyssus spp.,Ornithonyssus spp., Pneumonyssus spp.

from the order of the Prostigmata, for example, Cheyletiella spp.,Psorergates spp., Myobia spp., Demodex spp., Neotrombicula spp.;

from the order of the Astigmata, for example, Acarus spp., Myocoptesspp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp.,Notoedres spp., Knemidocoptes spp., Neoknemidocoptes spp., Cytoditesspp., Laminosioptes spp.

Particular emphasis may be given to the action against fleas(Siphonaptera, for example, Ctenocephalides spp., Echidnophaga spp.,Ceratophyllus spp., Pulex spp.), ticks (Hyalomma spp., Rhipicephalusspp., Boophilus spp., Amblyomma spp., Haemaphysalis spp., Dermacentorspp., Ixodes spp., Argas spp., Ornithodorus spp., Otobius spp.) and theDiptera mentioned above (Chrysops spp., Tabanus spp., Musca spp.,Hydrotaea spp., Muscina spp., Haematobosca spp., Haematobia spp.,Stomoxys spp., Fannia spp., Glossina spp., Lucilia spp., Calliphoraspp., Auchmeromyia spp., Cordylobia spp., Cochliomyia spp., Chrysomyiaspp., Sarcophaga spp., Wohlfartia spp., Gasterophilus spp., Oesteromyiaspp., Oedemagena spp., Hypoderma spp., Oestrus spp., Rhinoestrus spp.,Melophagus spp., Hippobosca spp.).

The useful and breeding animals include mammals, such as, for example,cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys,rabbits, fallow deer, reindeer, fur-bearing animals, such as, forexample, mink, chinchilla, racoon, birds, such as, for example, hens,geese, turkeys, ducks.

The laboratory animals and test animals include mice, rats, guinea pigs,rabbits, golden hamsters, dogs and cats.

The pets include dogs and cats.

Particular emphasis is given to application on cat and dog.

Application can take place both prophylactically and therapeutically.

Preferably, the liquid formulations according to the invention aresuitable for spot-on, pour-on or spray application, where the sprayapplication may be carried out, for example, using a pump spray or anaerosol spray (pressurized spray). For specific indications, theformulations may also be used after dilution with water as a dip; inthis case, the formulation should contain emulsifying additives.

The preferred application forms are pump spray, pour-on and spot-on. Thespot-on application is very particularly preferred.

The formulations according to the invention are distinguished by theirexcellent compatibility with customary “single-dose” plastic tubes andby their storage stability in various climate zones. They have lowviscosity and can be applied without any problems.

The liquid formulations according to the invention can be prepared bymixing appropriate amounts of the components with one another, using,for example, conventional stirring tanks or other suitable instruments.If required by the ingredients, it is also possible to operate under aprotective atmosphere or with other methods of excluding oxygen.

EXAMPLES Example 1

-   -   100 ml of liquid formulation consisting of    -   10.0 g of        5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole    -   57.30 g of diethylene glycol monoethyl ether    -   0.10 g of BHT    -   0.20 g of BHA    -   30.02 g of propylene carbonate    -   5.00 g of propylene glycol octanoate decanoate    -   0.24 g of flumethrin    -   10.36 g of MGK 264    -   0.02 g of citric acid

Example 2

-   -   100 ml of liquid formulation consisting of    -   10.00 g of        5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole    -   0.24 g of flumethrin    -   0.02 g of citric acid    -   0.20 g of BHT    -   68.00 g of dipropylene glycol monomethyl ether    -   13.40 g of propylene carbonate    -   5.00 g of demineralized water    -   5.00 g of propylene glycol octanoate decanoate    -   5.00 g of MGK 264

Example 3

-   -   100 ml of liquid formulation consisting of    -   10.00 g of        5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole    -   0.50 g of PPF (pyriproxyfen)    -   0.24 g of flumethrin    -   0.02 g of citric acid    -   0.20 g of BHT    -   67.50 g of dipropylene glycol monomethyl ether    -   13.40 g of propylene carbonate    -   5.00 g of demineralized water    -   5.00 g of propylene glycol octanoate decanoate    -   5.00 g of MGK 264

Example 4

-   -   100 ml of liquid formulation consisting of    -   10.00 g of        5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole    -   0.50 g of PPF (pyriproxyfen)    -   0.24 g of flumethrin    -   0.02 g of citric acid    -   0.20 g of BHT    -   60.90 g of diethylene glycol monoethyl ether    -   20.00 g of propylene carbonate    -   5.00 g of demineralized water    -   5.00 g of propylene glycol octanoate decanoate    -   5.00 g of MGK 264

Example 5

-   -   100 ml of liquid formulation consisting of    -   10.00 g of        5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole    -   45.00 g of permethrin    -   37.90 g of diethylene glycol monoethyl ether    -   0.10 g of BHT    -   0.20 g of BHA    -   25.00 g of propylene carbonate    -   5.00 g of propylene glycol octanoate decanoate    -   0.02 g of citric acid

Example 6

-   -   100 ml of liquid formulation consisting of    -   10.00 g of        5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole    -   45.00 g of permethrin    -   1.00 g of PPF    -   36.90 g of diethylene glycol monoethyl ether    -   0.10 g of BHT    -   0.20 g of BHA    -   25.00 g of propylene carbonate    -   5.00 g of propylene glycol octanoate decanoate    -   0.02 g of citric acid

Example 7

-   -   100 ml of liquid formulation consisting of    -   10.00 g of        5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole    -   45.00 g of permethrin    -   1.00 g of PPF    -   0.25 g of Silvet L 77 from GE Siliconocs GmbH D-51368 Leverkusen    -   36.65 g of diethylene glycol monoethyl ether    -   0.10 g of BHT    -   0.20 g of BHA    -   25.00 g of propylene carbonate    -   5.00 g of propylene glycol octanoate decanoate    -   0.02 g of citric acid

Example 8

-   -   10.00 g of        5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole    -   45.00 g of permethrin    -   1.00 g of PPF    -   0.25 g of Silvet L 77 (from Bayer-GE Silicones GmbH, D-51368        Leverkusen)    -   36.65 g of diethylene glycol monoethyl ether    -   0.10 g of BHT    -   0.20 g of BHA    -   25.00 g of ethylene carbonate    -   5.00 g of propylene glycol octanoate decanoate    -   0.02 g of citric acid

Comparative Example 1

A commercially available 10% fipronil spot-on formulation from MerialLtd., 3239 Satellite Blvd., Duluth, Ga. 30096-4640, USA.

Comparative Example 2

A formulation comprising5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-thiocarbamoylpyrazole,but without added flumethrin or MGK264:

-   -   100 ml of liquid formulation consisting of    -   10.00 g of        5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole    -   57.7 g of diethylene glycol monoethyl ether    -   40.0 g of propylene carbonate    -   5.0 g of propylene glycol octanoate decanoate    -   0.1 g of butylated hydroxytoluene    -   0.2 g of butylated hydroxyanisole

Comparative Example 3

A formulation comprising flumethrin and MGK264 and PPF, but, instead ofthe 3-thiocarbamoylpyrazole mentioned in the application, the knowninsecticide imidacloprid.

-   -   100 ml of liquid formulation consisting of    -   10.00 g of imidacloprid    -   0.50 g of PPF    -   56.80 g of benzyl alcohol    -   0.10 g of BHT    -   0.20 g of BHA    -   30.02 g of propylene carbonate    -   5.00 g of propylene glycol octanoate decanoate    -   0.24 g of flumethrin    -   10.36 g of MGK 264    -   0.02 g of citric acid

Biological Examples

All compounds were metered out exactly by weight to ensure bettercomparability. To this end, 20 pipettes of the fipronil-containingcommercial preparation were emptied into a glass bottle and likewiseblinded using a code.

All samples were applied as a single spot to the neck (cats and smallerdogs) using Eppendorf pipettes (volume up to 0.95 ml). For applicationvolumes of more than 1 ml, the volume was halved and applied to the neckas two spots at a distance of about 10 cm.

Further laboratory tests for the activity against fleas and ticksaccording to Example 2 show that the preparations in the abovementionedformulations according to the invention have very good and long-lastingaction against ticks and fleas which, in the tests, is consistentlysuperior to the prior art (CE1-CE3). Furthermore, the preparations inthe abovementioned formulations according to the invention aredistinguished in that they are tolerated by target animal and user, andthey are thus highly suitable for controlling fleas and ticks on smallanimals.

A. Activity against Fleas (Ctenocephalides felis) on Dogs

Between days −4 and −1, dogs are infested 1-2 times with about 100 adultunfed Ctenocephalides felis per dog. The fleas are placed on the neck ofthe animal. On day 0, the success of the infestation on the dog isexamined by checking the awake animal for fleas. The number of livefleas is noted.

After the fleas have been counted, the animals are treated. The dogs ofthe control group are not treated. The medicaments to be examined areadministered to the animals dermally as a spot-on in an application rateof 0.1-0.15 ml/kg of bodyweight or as a spray in an application rate of1-1.5 ml/kg of bodyweight. The application is carried out once on day 0.Only animals that are clinically healthy are used.

On days 1 and 2, all dogs are examined for live fleas. The results arenoted with the crude data.

On days 7, 14, 21, 28 and 35 and, if appropriate, also on days 42 and49, all dogs are reinfested with about 100 adult unfed Ctenocephalidesfelis per dog. In each case one day after the reinfestation, all dogsare checked for live fleas. The results are noted with the crude data.

A formulation is considered to be highly effective if, between 24 and 48hours after reinfestation, an efficacy of >95% is found, and this actionpersists for at least 3-4 weeks.

The efficacy is calculated using a modified formula according to Abbott:

${{Efficacy}\mspace{14mu} \%} = {\frac{{{number}{\mspace{11mu} \;}{of}\mspace{14mu} {fleas}\mspace{14mu} C\; G} - {{number}\mspace{14mu} {of}\mspace{14mu} {fleas}\mspace{14mu} T\; G}}{{number}\mspace{14mu} {of}{\mspace{11mu} \;}{fleas}\mspace{14mu} C\; G} \times 100}$

CG: control group; TG: treatment group

The medicaments of Formulation Example 2, applied as a spot-on at adosage of 0.15 ml/kg, were found to be highly effective againstCtenocephalides felis.

B. Activity against Ticks (Rhipicephalus sanguineus, Dermacentorvariabilis) on Dogs

Between days −4 and −1, dogs are sedated using 2% Rompun® (Bayer AG,active compound: xylazine hydrochloride) (0.1 ml/kg of bodyweight). Onceall dogs have been sedated (after about 10-15 minutes), they aretransferred to transport boxes, and 50 Rhipicephalus sanguineus orDermacentor variabilis (25

, 25

) per dog are applied to the neck of the animal. After about 1½ hours,the animals are retransferred from the transport box into the cage.

On day 0, the success of the infestation on the dog is examined bychecking the awake animal for ticks. An intensive search is carried outin the region of the head and the ears, including the folds of the ears,in the region of the neck, on the lower abdomen, on the lower breast, onthe flank and in between the toes and on the limbs.

The number of sucking live ticks is noted. Dead ticks are removed.

After the ticks have been counted, the animals are treated. The dogs ofthe control group are not treated. The medicaments to be examined areadministered to the animals dermally as a spot-on at 0.1-0.15 ml/kg ofbodyweight or as a spray at 1-1.5 ml/kg of bodyweight. The applicationis carried out once on day 0. Only animals which are clinically healthyare used.

On day 1 and day 2, all dogs are checked for living and dead suckingticks. The results are noted with the crude data. On day 2, all livingand dead ticks are removed from the dog.

On days 7, 14, 21, 28, 35 and, if appropriate, also on days 42 and 49,all dogs are reinfested with in each case 50 Rhipicephalus sanguineus orDermacentor variabilis (25

, 25

) per dog. In each case two days after the reinfestation, all dogs arechecked for living and dead sucking ticks. The results are noted withthe crude data. On the second day after the reinfestation, all livingand dead ticks are removed from the dog.

A formulation is considered to be highly effective if, on day 2 and ineach case on the second day after reinfestation, an efficacy of >90% isfound, and this action persists for at least 3 weeks.

For calculating the efficacy, a modified formula according to Abbott isused:

${{Efficacy}\mspace{14mu} \%} = {\frac{{{number}{\mspace{11mu} \;}{of}\mspace{14mu} {ticks}{\mspace{11mu} \;}C\; G} - {{number}\mspace{14mu} {of}\mspace{14mu} {ticks}{\mspace{11mu} \;}T\; G}}{{number}\mspace{14mu} {of}{\mspace{11mu} \;}{ticks}\mspace{14mu} C\; G} \times 100}$

CG: control group; TG: treatment group

The medicaments according to Formulation Example 2, applied as a spot-onat a dosage of 0.15 ml/kg, were found to be highly effective againstRhipicephalus sanguineus.

C. Activity against Fleas (Ctenocephalides felis) on Cats

On day −1, cats are infested with about 100 adult unfed Ctenocephalidesfelis per cat. The fleas are placed on the neck of the animal.

On day 0, the success of the infestation on the cat is examined bychecking the awake animal for fleas. The number of live fleas is noted.

After the fleas have been counted, the animals are treated. The cats ofthe control group are not treated. The medicaments to be examined areadministered to the animals dermally as a spot-on in an application rateof 0.1-0.15 ml/kg of bodyweight. The application is carried out once onday 0. Only animals that are clinically healthy are used.

On day 2, all cats are examined for live fleas. The results are notedwith the crude data.

On days 7, 14, 21, 28 and 35 and, if appropriate, also on days 42 and49, all cats are reinfested with about 100 adult unfed Ctenocephalidesfelis per cat. In each case two days after reinfestation, all cats arechecked for live fleas. The results are noted with the crude data.

A formulation is considered to be highly effective if, on day 2 and ineach case on the second day after reinfestation, an efficacy of >95% isfound, and this action persists for at least 3-4 weeks.

The efficacy is calculated using a modified formula according to Abbott:

${{Efficacy}\mspace{14mu} \%} = {\frac{{{number}{\mspace{11mu} \;}{of}\mspace{14mu} {fleas}\mspace{14mu} C\; G} - {{number}\mspace{14mu} {of}\mspace{14mu} {fleas}\mspace{14mu} T\; G}}{{number}\mspace{14mu} {of}{\mspace{11mu} \;}{fleas}\mspace{14mu} C\; G} \times 100}$

CG: control group; TG: treatment group

The medicaments of Formulation Example 2, applied as a spot-on at adosage of 0.15 ml/kg, were found to be highly effective againstCtenocephalides felis.

D. Activity against Ticks (Ixodes ricinus) on Cats

In each case on day −2, cats are sedated using a mild sedative(acepromazine maleate). Once all cats have been sedated (after about10-15 minutes), 30-50 Ixodes ricinus (15-25

, 15-25

) per cat are applied to the neck of the animal.

On day −1, the success of the infestation on the cats is examined bychecking the awake animal for ticks. An intensive search is carried outin the region of the head and the ears, in the region of the neck, onthe lower abdomen, on the lower breast, on the flank and on the limbs.The number of sucking live ticks is noted. Dead ticks are removed.

After the ticks have been counted, the animals are divided into groups.Treatment is carried out on day 0. The cats of the control group are nottreated. The medicaments to be examined are administered to the animalsdermally, as a spot-on at 0.1-0.15 ml/kg of bodyweight. Application iscarried out once on day 0. Only animals which are clinically healthy areused.

On day 2, all cats are checked for living and dead sucking ticks. Theresults are noted with the crude data. All living and dead ticks areremoved from the cat.

On days 7, 14, 21, 28 and 35 and, if appropriate, also on days 42 and49, all cats are reinfested with in each case 30-50 Ixodes ricinus(15-25

, 15-25

) per cat. In each case two days after the reinfestation, all cats arechecked for living and dead sucking ticks. The results are noted withthe crude data. On the second day after the reinfestation, all livingand dead ticks are removed from the cat.

A formulation is considered to be highly effective if, on day 2 and ineach case on the second day after reinfestation, an efficacy of >90% isfound, and this action persists for at least 3 weeks.

For calculating the efficacy, a modified formula according to Abbott isused:

${{Efficacy}\mspace{14mu} \%} = {\frac{{{number}{\mspace{11mu} \;}{of}\mspace{14mu} {ticks}{\mspace{11mu} \;}C\; G} - {{number}\mspace{14mu} {of}\mspace{14mu} {ticks}{\mspace{11mu} \;}T\; G}}{{number}\mspace{14mu} {of}{\mspace{11mu} \;}{ticks}\mspace{14mu} C\; G} \times 100}$

CG: control group; TG: treatment group

The medicaments according to Formulation Example 2, applied as a spot-onat a dosage of 0.15 ml/kg, were found to be highly effective againstIxodes ricinus.

E. Efficacy against Fleas and Ticks over 4 to 7 Weeks

The efficacy of the compositions according to the invention againstfleas and ticks was tested over a period of four to seven weeks. Thetest was carried out according to the description under items A to D.

TABLE 1a Efficacy of the composition according to Example 2 againstfleas on cats Appl. 10 Vol W0 WD W2 W3 W4 W5 Treatment ml/kg Parasite D2D9 D16 D23 D30 D37 1. CE 1 0.1 Ctenocephalides 97 2. 100 3. 100 4. 1005. 99 6. 100 infes- felis infestation infestation infestationinfestation infestation tation CE 2 0.15 Ctenocephalides 99 day 7 100day 14 100 day 21 100 day 28 100 day 35 99 day - 4 felis Example 2 0.15Ctenocephalides 99 100 100 100 100 100 felis CE 3 0.1 Ctenocephalides100 100 100 99 94 74 felis

TABLE 1b Efficacy of the composition according to Example 2 againstticks on cats Appl. 10 Vol W0 WD W2 W3 W4 W5 Treatment ml/kg Parasite D2D9 D16 D23 D30 D37 1. CE 1 0.1 Ixodes ricinus 74 2. 99 3. 96 4. 72 5. 826. 89 infestation CE 2 0.15 Ixodes ricinus 84 infestation 99 infestation92 infestation 84 infestation 73 infestation 68 day - 4 Example 2 0.15Ixodes ricinus 70 day 7 100 day 14 100 day 21 97 day 28 100 day 35 95 CE3 0.1 Ixodes ricinus 71 100 100 96 93 76 Appl. Vol = volume applied inml/kg of bodyweight “value” % = efficacy in %, calculated viadetermination of the geometrical mean compared to an untreated controlgroup

TABLE 2a Efficacy of the composition according to Example 2 againstfleas on dogs D0 Appl. Vol W0 W1 W2 Treatment ml/kg Parasite D2 D9D16 1. infestation 2. infestation day - 1 CE 1 0.1 Ctenocephalides felis100 3. infestation day 7 100 4. infestation day 14 100 day - 4 CE 2 0.15Ctenocephalides felis 100 100 100 Example 2 0.15 Ctenocephalides felis100 99 100 CE 3 0.1 Ctenocephalides felis 100 100 100 W3 W4 W5 W6 W7 D23D30 D37 D44 D51 5. infestation day 21 99 6. infestation day 28 99 7.infestation day 35 100 8. infestation day 42 62 9. infestation day 49 33100 100 99 99 76 100 100 100 100 77 100 98 74 nd nd

TABLE 2b Efficacy of the composition according to Example 2 againstticks on dogs D0 Appl. Vol W0 W1 W2 Treatment ml/kg Parasite D2 D9D16 1. infestation 2. infestation CE 1 0.1 Rhipicephalus sanguineus 973. infestation day 7 100 4. infestation day 14 100 day - 4 day - 1 CE 20.15 Rhipicephalus sanguineus 96 100 100 Example 2 0.15 Rhipicephalussanguineus 92 100 100 CE 3 0.1 Rhipicephalus sanguineus 60 94 99 W3 W4W5 W6 W7 D23 D30 D37 D44 D51 5. infestation day 21 100 6. infestationday 28 99 7. infestation day 35 94 8. infestation day 42 93 9.infestation day 49 65 100 100 99 98 74 100 100 99 99 88 98 98 91 nd ndAppl. Vol = volume applied in ml/kg of bodyweight “value” % = efficacyin %, calculated via determination of the arithmetic mean compared to anuntreated control group

TABLE 3 Efficacy of the composition according to Example 2 against tickson dogs D0 Appl. Vol W0 W1 W2 W3 W4 Treatment ml/kg Parasite D2 D9 D16D23 D30 1. CE 1 0.15 Dermacentor variabilis 25 2. 98 3. 99 4.infestation 100 5. infestation 98 infestation Example 2 0.15 Dermacentorvariabilis 55 infestation 100 infestation 99 day 21 100 day 28 100 day -4 CE 3 0.1 Dermacentor variabilis 34 day 7 89 day 14 80 66 87 Appl. Vol= volume applied in ml/kg of bodyweight “value” % = efficacy in %,calculated via determination of the geometrical mean compared to anuntreated control group

1. A composition for controlling parasites on animals, comprising: a. anN-arylpyrazole; b. a pyrethroid; c. an aliphatic cyclic carbonate; and,d. an aliphatic cyclic or acyclic polyether.
 2. The composition of claim1, further comprising an ester of a dihydric or trihydric alcohol havingup to three carbon atoms with organic fatty acids having 6 to 18 carbonatoms.
 3. The composition of claim 1, wherein the N-arylpyrazolecomprises from 1 to 27.5% by weight of the composition.
 4. Thecomposition of claim 1, wherein the aliphatic cyclic carbonate comprisesfrom 10 to 70% by weight of the composition.
 5. The composition of claim1, wherein the aliphatic cyclic or acyclic polyether comprises from 20to 77.5% by weight of the composition.
 6. The composition of claim 1,wherein the pyrethroid is an α-cyanopyrethroid.
 7. The composition ofclaim 6, wherein the α-cyanopyrethroid is selected from the groupconsisting of alpha-cypermethrin, cyfluthrin, beta-cyfluthrin,cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucythrinate,flumethrin, and tau-fluvalinate.
 8. The composition of claim 1, whereinthe pyrethroid is a type 1 pyrethroid.
 9. The composition of claim 8,wherein the type 1 pyrethroid is selected from the group consisting ofallethrin, bioallethrin, permethrin, phenothrin, resmethrin,tetramethrin and transfluthrin.
 10. The composition of claim 1, whereinthe pyrethroid is a non-ester pyrethroid.
 11. The composition of claim10, wherein the non-ester pyrethroid is selected from the groupconsisting of etofenprox, halfenprox, silafluofen.
 12. (canceled) 13.The composition of claim 1, wherein the N-arylpyrazole is selected fromthe group consisting of pyriprole, pyrafluprole,5-amino-4-trifluoromethyl-sulphinyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-thiocarbamoylpyrazole,vanilliprole, fipronil, ethiprole, and acetoprole.
 14. The compositionof claim 1, wherein the N-arylpyrazole is fipronil.
 15. The compositionof claim 1, wherein the N-arylpyrazole comprises from 7.5 to 15% byweight of the composition.
 16. The composition of claim 1, wherein thecyclic carbonate is selected from the group consisting of ethylenecarbonate, propylene carbonate, or mixtures thereof.
 17. The compositionof claim 1, wherein the aliphatic cyclic carbonate comprises from 15 to40% by weight of the composition.
 18. The composition of claim 1,wherein the aliphatic cyclic or acyclic polyether is selected from thegroup consisting of monoethyl ether, diethylene glycol monopropyl ether,dipropylene glycol monopropyl ether, and tetrahydrofurfuryl alcohol. 19.The composition of claim 1, wherein the aliphatic cyclic or acyclicpolyether comprises from 25 to 50% by weight of the composition.
 20. Amethod of controlling parasites in parasite infested animals, whichcomprises applying to said animals an effective amount of thecomposition of claim
 1. 21. The method of claim 14, wherein the animalis selected from cats and dogs and wherein the parasite is selected fromthe group consisting of fleas and ticks.